The invention relates to new C-19-halogen-substituted steroids of the androst-9(11)-ene series, namely 17xcex2-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I, and process for their production. In addition, the use of the new radiohalogen-labeled compounds of Formula I as radio-pharmaceutical agents is the subject of the invention. These compounds can be used especially preferably in diagnostic studies of the prostate.
Moreover, the invention relates to the use of non-labeled compounds of Formula I as starting products for the production of new biologically active 5xcex2-substituted androst-9(11)-enes of general formula II and the new 6xcex2,19-cycloandrosta-4,9(11)-dienes of Formula III as well as processes for their production and use.
The basic attempt to develop diagnostically and therapeutically usable agents by radioactive labeling of testosterone (17xcex2-hydroxyandrost-4-en-3-one) is known in the literature (S. J. Brandes and J. E. Katzenellenbogen, Nucl. Med. Biol. 15, 53-67, 1988). The previously used testosterone derivatives have not been introduced into clinical practice, however, in particular because of insufficient tissue selectivity and metabolic instability.
The object of this invention was therefore to find new compounds that are better suited for radiodiagnostic processes.
New 17xcex2-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I were found that are distinguished by a surprisingly high affinity to the androgen receptor Formula I 
in which
X=a halogen or radiohalogen radical, preferably Br, I, 125I, 131I, 82Br or 77Br.
The compound 17xcex2-hydroxy-19-125iodo-androsta-4,9(11)-dien-3-one represents a preferred radiopharmaceutical agent. The compounds 17xcex2-hydroxy-19-iodo-androsta-4,9(11)-dien-3-one and 19-bromo-17xcex2-hydroxy-androsta-4,9(11)-dien-3-one also show a high affinity to the androgen receptor.
The new compounds of general formula I are suitable in particular in the form of the radiohalogen-labeled derivatives for diagnostic use, preferably for graphic visualization of the prostate and for early detection of pathophysiological changes thereof.
The compounds according to the invention are distinguished from known derivatives of testosterone (J. N. Wright et al., J. Chem. Soc. Perkin/1989, 1647-1655) by a 9(11)-double bond. This structural element opens up the possibility of introducing a functional group at C-19 by a process that is advantageously distinguished from the standard methods for functionalizing a C-19-methyl group (J. Kalvoda et al., Helv. Chim. Acta 46, 1361, 1963 and M. Akhtar and D. H. R. Barton, J. Am. Chem. Soc. 88, 1528, 1964).
The production of the 17xcex2-hydroxy-19-halogen-androsta-4,9(11)-dien-3-ones of general formula I according to the invention is carried out according to claim 4, and dependent claims 5 to 8 are preferred variants.
Diagram 1 below shows the synthesis methods according to the invention in the example of 17xcex2-hydroxy-19-iodo-androsta-4,9(11)-dien-3-one. 
The starting material is aldehyde 1 that is known in the literature (3,3-(2,2-dimethyl-trimethylenedioxy)-10xcex2-formyl-androst-9(11)-ene-5xcex1,17xcex2-diolxe2x80x94G. Neef et al., Tetrahedron 49, 833-840, 1993), which was used for the production of C-19-iodide 7. 
Surprisingly enough, however, the known compound 7 is not suitable for the production of an end product of Formula I according to the invention. Under the conditions of the usual deketalization/dehydration as well as the subsequent ester saponification at C-17, the C-19-iodine substitution is not maintained.
Only the process that is outlined in Diagram 1 ensures the production of the end products in high yields and purity and allows for the synthesis of the target compounds of general formula I.
In a first step of the process according to the invention, first the C-17xcex2-hydroxy group is protected by silylation with the formation of intermediate product 2. With hydride-transferring reagents, such as, e.g., with sodium borohydride or lithium aluminum hydride, compound 2 is reduced to alcohol 3 in a way that is common in the art. Under conditions described by Neef et al. (Tetrahedron 49, 833, 1993), alcohol 3 is then further reacted to form iodide 4, whereby only a slight excess of elementary iodine must be used for reaction. Especially when the process is carried out with transfer of the reaction sequence to radiolabeled end compounds, this can be regarded as a special advantage.
Although conceivable in principle, iodide 4 cannot be converted directly into end product 6 of general formula I by treatment with acid in a one-stage process. Having the process according to the invention proceed in steps is essential to the success of the process.
First, under standard conditions (e.g., with thionyl chloride/pyridine), dehydration is performed, which results in the formation of a mixture of double-bond isomers 5a and 5b. In a separate subsequent step, mixture 5a, b is then converted smoothly into target compound 6 (Formula I with X=I) without prior separation. This final synthesis step, which contains the cleavage of the 3-ketal grouping and the silyl ether cleavage at C-17xcex2, is preferably performed with a strong protonic acid such as trifluoroacetic acid or sulfuric acid.
The synthesis that is shown in the example of iodine for radical X of general formula I is also performed analogously for the production of bromide or the radiolabeled halides.
By the use of almost stoichiometric amounts of halogens, in particular when using radiohalogens, the process according to the invention is not only economical and environmentally safe, but it also makes possible the production of end compounds with high specific activity.
The substances of general formula I bind with high affinity to the androgen receptor despite a voluminous halogen substituent at the C-19 position.
Because of their biochemical and pharmacokinetic properties, the compounds according to the invention are extremely well suited for use in diagnostic processes.
Thus, e.g., iodide 6 (Formula I, X=I) with an IC50 value of 57 nmol/l shows a slight weakening of the binding affinity in comparison to the reference standard (3H-methyltrienolone R 1881), but it remains in an order of magnitude that shows a large degree of specific binding to the human androgen receptor in the prostate tissue.
The graphic visualization of the prostate requires, however, not only a large degree of specific binding, but it also requires little or almost no binding to transport proteins in the serum (S. J. Brandes and J. E. Katzenellenbogen, Nucl. Med. Biol. 15, 53-67, 1988). Decisive serum protein for the transport of androgens is SHBG (steroid hormone binding globulin). The SHBG affinity of iodide 6 compared to the standard DHT (5xcex1-dihydrotestosterone) is reduced by a factor of 197. Thus, another requirement for the contrast-rich imaging of androgen-receptor-containing tissue is met.
The subject of the invention is therefore also the use of the compounds of general formula I as a diagnostic agent according to claims 9 and 10. A preferred use is carried out for graphic visualization of the prostate and for early detection of pathophysiological changes thereof.
In addition to the use for diagnostic purposes, the non-labeled compounds of Formula I according to the invention are also valuable starting products for the production of new, unusual substituted steroids according to claim 11.
The silylation of the 17xcex2-hydroxy group of the C-19-halogen-substituted steroids of the androst-9(11)-ene series according to the invention thus results in a 17xcex2-silyl ether of general formula Ia 
in which X=halogen, selected from Br, I, and which represents an important intermediate product for the further synthesis in a so-called tandem process to the new compounds of general formula II. Moreover, the intermediate products of formula Ia are used for the production of the new 6xcex2,19-cycloandrosta-4,9(11)-dienes of general formula III.
Shown in the example of 17xcex2-(tert-butyltrimethylsilyloxy)-19-iodo-androsta-4,9(11)-dien-3-one 8, the reaction with mercaptoacetic acid methyl ester in the presence of a suitable base thus results in the formation of a thia-bridged derivative 9. Starting products can also be the other non-labeled 17xcex2-silylated C-19-halogen derivatives. 
In this way, the functional group at C-19 is used to achieve a C-C linkage with the tertiary position C-5. Of course, the stereoselective introduction of functional groups in the tertiary positions of the steroid skeleton is a problem of preparative chemistry, for which general solutions are not available. Thus, specifically the introduction of a 5xcex2-methyl group by reaction of testosterone with organometallic reagents is known (e.g., C. Petrier et al., Tetrahedron Lett. 25, 3463, 1984), but is not suitable for the introduction of higher alkyl substituents or functionally substituted alkyl groups.
Thia-bridged derivative 9 is then reacted to form compounds of general formula II 
with a radical R in the meaning of:
R=xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94R1, xe2x80x94(CH2)nCH2xe2x80x94OR1, xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94OCOR1, xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94SR1, xe2x80x94(CH2)nxe2x80x94CH2xe2x80x94NR1R2, xe2x80x94(CH2)nxe2x80x94CHO, xe2x80x94(CH2)nxe2x80x94CN
in which n can assume the values of 0-5, and radicals R1 and R2, independently of one another, stand for hydrogen or a straight-chain or branched, saturated or unsaturated hydrocarbon radical with up to 18 C atoms, whereby this radical optionally can contain additional functional groups and carbocyclic or heterocyclic ring elements.
According to the empirical findings from the normal series (9(11)-saturated) described in the literature, the result of the reaction of silylated halide Ia, e.g., iodide 8, with mercaptoacetic acid methyl ester was not predictable. As described by Halpern et al. (Steroids 4, 1-30, 1964), Santaniello and Caspi (J. Steroid Biochem. 7, 223-227, 1976) and Wright et al. (J. Chem. Soc. Perkin Trans. I, 1989, 1647-1655), the nucleophilic substitution at C-19 in the presence of the 3-oxo-4-ene structural element is extremely hampered and mainly results in skeletal restructuring.
All the more surprising is the smooth course of the reaction of a compound of Formula Iaxe2x86x92thia-bridged derivative 9, which can be interpreted mechanistically as a nucleophilic halogen-sulfur exchange with subsequent Michael addition (tandem process).
Diagram 2 illustrates a synthesis method by way of example: 
The process that is described by Diagram 2 offers a number of possibilities for producing derivatives of general formula II. It is obvious that, e.g., intermediate products 13 and 14 produce an abundance of compounds for the production of such new steroids.
The compounds of general formula II are a new class of antiandrogenically active steroids and thus are suitable for the treatment of androgen-dependent diseases (prostate carcinoma, prostate hyperplasia).
The subjects of the invention are therefore also the compounds of general formula II according to claim 12, process for their production according to claim 13 and their use according to claim 14.
The new compounds of general formula III are produced according to claim 17 from the 17xcex2-silyl ether of general formula Ia.
The treatment of silylated iodide 8 of general formula Ia with a non-nucleophilic base (e.g., sodium hydride, triethylamine, fluoride) in an aprotic solvent (e.g., THF, DMF) results in the formation of cyclosteroid 18. 
After conventional silyl ether cleavage (tetrabutylammonium fluoride), the new testosterone derivative 19, the 17xcex2-hydroxy-6xcex2,19-cycloandrosta-4,9(11)-dien-3-one, is produced. By standard processes (esterification, etherification, oxidation), 19 is converted in a simple way into additional compounds of general formula III, which are distinguished by aromatase- and 5xcex1-reductase inhibiting action.
The subjects of the invention are consequently also the new 6xcex2,19-cycloandrostadienes of formula III of claim 16, as well as processes for their production and their use according to claim 21. 
in which
X=O or the grouping 17xcex2-OR, 17xcex1-H, with R in the meaning of H, C1-C10-alkyl, C1-C10-acyl, whereby the acyl radical is derived from an aliphatic or aromatic carboxylic acid.
In addition, the subjects of the invention are the 17xcex2-silyl ether of general formula Ia, which are produced as intermediate products from the compounds of general formula I according to the invention and common starting products for the new 5xcex2-substituted steroids of general formula II and the 6xcex2,19-cycloandrostadienes of Formula III.
The invention also includes pharmaceutical agents according to claim 24, which as active components contain at least one compound of general formula I, II and/or III.
The examples below are to explain the invention in more detail, without limiting the latter thereto.